Hydrogen sulfide (H2S) is a well-known colorless, toxic and lethal gas with the smell of rotten eggs. It is water soluble as well as lipophilic and can therefore be transported rapidly between cells and tissues. Together with nitric oxide (NO) and carbon monoxide (CO), H2S belongs to the gasotransmitter family and plays an important role in mammalian systems as a signaling molecule. Therefore, H2S has promising medical and pharmaceutical applications.
As an endogenous gasotransmitter, hydrogen sulfide is known to reduce inflammatory processes such as edema, cytokine synthesis, and leukocyte adherence to the endothelium. It has been reported that hydrogen sulfide reduces the risk of gastric injury due to ulceration and accelerates repair. Therefore, H2S releasing agents coupled with non-steroidal anti-inflammatory drugs present prospects for improved gastrointestinal safety, parent-drug potency and overall drug efficacy along with reduced the adverse effects associated with NSAIDs.
Several studies have reported various H2S donors, which include, garlic and related sulfur compounds; Lawesson's reagent and analogs (e.g., GYY4137); 1,2-dithiole-3-thiones (DTTs) and hybrids of H2S and non-steroidal anti-inflammatory drugs; thiol-activated H2S donors; photo-induced H2S donors; and thiolamino acids. There are several limitations reported for these H2S donors. Most suffer from drawbacks such as uncontrollable or fixed and inflexible release rates. Others, having controllable H2S donors, such as thiol-activated H2S donors, consume free thiols in biological systems, which can cause changes in thiol redox balance. H2S donors that can afford a slow and continuous release of H2S mimicking the endogenous H2S production through enzymatically controlled processes are currently not available.
Therefore, there is a need for new H2S donors, which generate H2S in vivo and in vitro controllably without the need for harmful external stimuli (e.g., UV light) or consumption of biological nutrients which could affect the homeostasis of other important biological species. The present invention provides new H2S donors that meet this need, providing significant advantages for medical, pharmaceutical and research applications.